US6465504B1 - Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators - Google Patents

Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators Download PDF

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US6465504B1
US6465504B1 US09/699,765 US69976500A US6465504B1 US 6465504 B1 US6465504 B1 US 6465504B1 US 69976500 A US69976500 A US 69976500A US 6465504 B1 US6465504 B1 US 6465504B1
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lower alkyl
bis
hydroxyphenyl
triazol
alkylamino
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René Lattmann
Pierre Acklin
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Novartis AG
Norvartis AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/04—Chelating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • iron overload (formerly haemosiderosis). It occurs, e.g., after parenteral administration of iron (especially repeated blood transfusions) or after increased uptake of iron from the gastrointestinal tract. Repeated transfusions are necessary in serious anemias, especially in thalassaemia major, the severe form of ⁇ -thalassaemia, but also in other anemias.
  • Increased iron absorption from the gastrointestinal tract either takes place primarily, e.g. on account of a genetic defect (so-called haemochromatosis), or secondarily, such as after anemias in which blood transfusions are not necessary, e.g. thalassaemia intermedia, a milder form of ⁇ -thalassaemia.
  • Untreated iron overload can cause severe organ damage, in particular of the liver, the heart and the endocrine organs, and can lead to death.
  • Iron chelators are able to mobilize and excrete the iron deposited in the organs and thus lower the iron-related morbidity and mortality.
  • a reduction in the iron(III) concentration is also of interest for the treatment of disorders due to iron(III)-dependent microorganisms and parasites, which is of key importance not only in human medicine, such as in particular in malaria, but also in veterinary medicine.
  • Complexing of other metals, in particular trivalent metals, can also be used for excretion thereof from the organism.
  • a number of further applications are also described in the literature, e.g. by Kontoghiorghes, Toxicology Lett. 80:1-18 (1995).
  • Desferrioxamine B has already been known for a long time and used therapeutically for these purposes [Bickel et al., Helv. Chim. Acta 46:1385-1389 (1963)].
  • a disadvantage of this preparation turns out to be the fact that desferrioxamine and its salts only have a low, inadequate activity on oral administration and require a parenteral administration form in all of the abovementioned application possibilities. It is thus recommended, e.g., as a particularly effective method to administer the active substance by means of a slow (8 to 12 hour) subcutaneous infusion, which, however, demands the use of a portable mechanical device, such as an infusion syringe actuated by an electrical drive.
  • a portable mechanical device such as an infusion syringe actuated by an electrical drive.
  • the present invention relates to the use of compounds of the formula I
  • R 1 and R 5 simultaneously or independently of one another are hydrogen, halogen, hydroxyl, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, carboxyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or nitrile;
  • R 2 and R 4 simultaneously or independently of one another are hydrogen, unsubstituted or substituted lower alkanoyl or aroyl, or a radical which can be removed under physiological conditions, e.g.
  • R 3 is hydrogen, lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, R 6 R 7 N—C(O)-lower alkyl, unsubstituted or substituted aryl or aryl-lower alkyl, or unsubstituted or substituted heteroaryl or heteroaralkyl; R 6 and R 7 simultaneously or independently of one another are hydrogen, lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, hydroxyalkoxy-lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, N-(hydroxy-lower alkyl)amino-lower alkyl, N,N-di(hydroxy-lower alkyl)amino-lower alkyl, N
  • Halogen is, e.g., chlorine, bromine or fluorine, but can also be iodine.
  • the prefix “lower” designates a radical having not more than 7 and in particular not more than 4 carbon atoms.
  • Alkyl is straight-chain or branched. Per se, e.g. lower alkyl, or as a constituent of other groups, e.g. lower alkoxy, lower alkylamine, lower alkanoyl, lower alkylaminocarbonyl, it can be unsubstituted or substituted, e.g. by halogen, hydroxyl, lower alkoxy, trifluoromethyl, cyclo-lower alkyl, azaalicyclyl or phenyl, it is preferably unsubstituted or substituted by hydroxyl.
  • lower alkyl or as a constituent of other groups, e.g. lower alkoxy, lower alkylamine, lower alkanoyl, lower alkylaminocarbonyl, it can be unsubstituted or substituted, e.g. by halogen, hydroxyl, lower alkoxy, trifluoromethyl, cyclo-lower alkyl, azaalicyclyl or phenyl, it
  • Lower alkyl is, e.g., n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably methyl, ethyl and n-propyl.
  • Halo-lower alkyl is lower alkyl substituted by halogen, preferably chlorine or fluorine, in particular by up to three chlorine or fluorine atoms.
  • Lower alkoxy is, e.g., n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-amyloxy, isoamyloxy, preferably methoxy and ethoxy.
  • Halo-lower alkoxy is lower alkoxy substituted by halogen, preferably chlorine or fluorine, in particular by up to three chlorine or fluorine atoms.
  • Carbamoyl is the radical H 2 N—C(O)—, N-lower alkylcarbamoyl is lower alkyl-HN—C(O)—and N,N-di-lower alkylcarbamoyl is di-lower alkyl-N—C(O)—.
  • Lower alkanoyl is HC(O)— and lower alkyl-C(O)— and is, e.g., acetyl, propanoyl, butanoyl or pivaloyl.
  • Lower alkoxycarbonyl designates the radical lower alkyl-O—C(O)— and is, e.g., n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-amyloxycarbonyl, isoamyloxycarbonyl, preferably methoxycarbonyl and ethoxycarbonyl.
  • Aryl per se, e.g. aryl, or as a constituent of other groups, e.g. aryl-lower alkyl or aroyl, is, e.g., phenyl or naphthyl, which is substituted or unsubstituted.
  • Aryl is preferably phenyl which is unsubstituted or substituted by one or more, in particular one or two, substituents, e.g.
  • lower alkyl lower alkoxy, hydroxyl, nitro, halogen, trifluoromethyl, carboxyl, lower alkoxycarbonyl, amino, N-lower alkylamino, N,N-di-lower alkylamino, aminocarbonyl, lower alkylaminocarbonyl, di-lower alkylaminocarbonyl, heterocycloalkyl, heteroaryl or cyano.
  • aryl is unsubstituted phenyl or naphthyl, or phenyl which is substituted by lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, lower alkoxycarbonyl, N, N-di-lower alkylamino or heterocycloalkylcarbonyl.
  • Aroyl is the radical aryl-C(O)— and is, e.g., benzoyl, toluoyl, naphthoyl or p-methoxybenzoyl.
  • Aryl-lower alkyl is, e.g., benzyl, p-chlorobenzyl, o-fluorobenzyl, phenylethyl, p-tolylmethyl, p-dimethylaminobenzyl, p-diethylaminobenzyl, p-cyanobenzyl, p-pyrrolidinobenzyl.
  • Heterocycloalkyl designates a cycloalkyl radical having 3 to 8, in particular having from 5 to not more than 7, ring atoms, of which at least one is a heteroatom; oxygen, nitrogen and sulfur are preferred.
  • Azaalicyclyl is a saturated cycloalkyl radical having 3-8 in particular 5-7, ring atoms, in which at least one of the ring atoms is a nitrogen atom.
  • Azaalicyclyl can also contain further ring heteroatoms, e.g. oxygen, nitrogen or sulfur; it is, e.g., piperidinyl, piperazinyl, morpholinyl or pyrrolidinyl.
  • Azaalicyclyl radicals can be unsubstituted or substituted by halogen or lower alkyl.
  • the azaalicyclyl radicals bonded via a ring nitrogen atom, which are preferred, are, as is known, designated as piperidino, piperazino, morpholino, pyrrolidino etc.
  • Heteroaryl per se e.g. heteroaryl, or as a constituent of other substituents, e.g. heteroaryl-lower alkyl, is an aromatic radical having from 3 to not more than 7, in particular from 5 to not more than 7, ring atoms, in which at least one of the ring atoms is a heteroatom, e.g. pyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, furanyl, thiophenyl, pyridyl, pyrazinyl, oxazinyl, thiazinyl, pyranyl or pyrimidinyl.
  • pyrrolyl imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, furanyl, thiophenyl, pyridyl, pyrazinyl, oxazinyl,
  • Heteroaryl can be substituted or unsubstituted. Heteroaryl which is unsubstituted or substituted by one or more, in particular one or two, substituents, e.g. lower alkyl, halogen, trifluoromethyl, carboxyl or lower alkoxycarbonyl, is preferred.
  • substituents e.g. lower alkyl, halogen, trifluoromethyl, carboxyl or lower alkoxycarbonyl
  • Heteroaryl-lower alkyl designates a lower alkyl radical in which at least one of the hydrogen atoms, preferably on the terminal C atom, is replaced by a heteroaryl group if the alkyl chain contains two or more carbon atoms.
  • N-lower alkylamino is, e.g., n-propylamino, n-butylamino, i-propylamino, i-butylamino, hydroxyethylamino, preferably methylamino and ethylamino.
  • the alkyl substituents can be identical or different.
  • N,N-di-lower alkylamino is, e.g., N,N-dimethylamino, N,N-diethylamino, N,N-methylethylamino, N-methyl-N-morpholinoethylamino, N-methyl-N-hydroxyethylamino or N-methyl-N-benzylamino.
  • Salts of compounds of the formula I are, in particular, pharmaceutically acceptable salts, especially salts with bases, such as appropriate alkali metal or alkaline earth metal salts, e.g. sodium, potassium or magnesium salts, pharmaceutically acceptable transition metal salts such as zinc salts, or salts with organic amines, such as cyclic amines, such as mono-, di- or tri-lower alkylamines, such as hydroxy-lower alkylamines, e.g. mono-, di- or trihydroxy-lower alkylamines, hydroxy-lower alkyl-lower alkylamines or polyhydroxy-lower alkylamines.
  • bases such as appropriate alkali metal or alkaline earth metal salts, e.g. sodium, potassium or magnesium salts
  • pharmaceutically acceptable transition metal salts such as zinc salts
  • organic amines such as cyclic amines, such as mono-, di- or tri-lower alkylamines, such as hydroxy-lower alkyl
  • Cyclic amines are, e.g., morpholine, thiomorpholine, piperidine or pyrrolidine.
  • Suitable mono-lower alkylamines are, e.g., ethyl- and tert-butylamine; di-lower alkylamines are, e.g., diethyl- and diisopropylamine; and tri-lower alkylamines are, e.g., trimethyl- and triethylamine.
  • hydroxy-lower alkylamines are, e.g., mono-, di- and triethanolamine; hydroxy-lower alkyl-lower alkylamines are, e.g., N,N-dimethylamino- and N,N-diethylaminoethanol; a suitable polyhydroxy-lower alkylamine is, e.g., glucosamine.
  • acid addition salts e.g. with strong inorganic acids, such as mineral acids, e.g. sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as lower alkanecarboxylic acids, e.g.
  • acetic acid such as saturated or unsaturated dicarboxylic acids, e.g. malonic, maleic or fumaric acid, or such as hydroxycarboxylic acids, e.g. tartaric or citric acid, or with sulfonic acids, such as lower alkane- or substituted or unsubstituted benzenesulfonic acids, e.g. methane- or p-toluenesulfonic acid.
  • Compounds of the formula I having an acidic group, e.g. carboxyl, and a basic group, e.g. amino can also be present in the form of internal salts, i.e. in zwitterionic form, or a part of the molecule can be present as an internal salt, and another part as a normal salt.
  • the invention relates to the use of a compound of formula I for the treatment of diseases which cause an excess of iron in the human or animal body or are caused by it, preferably in the form of pharmaceutically acceptable preparations, in particular in a method for the therapeutic treatment of the human body, and to a treatment method of this type.
  • the invention relates to novel preparations, comprising at least one compound of the formula I, in which
  • R 1 and R 5 simultaneously or independently of one another are hydrogen, halogen, hydroxyl, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, carboxyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or nitrile;
  • R 2 and R 4 simultaneously or independently of one another are hydrogen, unsubstituted or substituted lower alkanoyl or aroyl, or a radical which can be removed under physiological conditions, e.g.
  • R 3 is hydrogen, lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, R 6 R 7 N—C(O)-lower alkyl, unsubstituted or substituted aryl, aryl-lower alkyl, substituted by N-lower alkylamino, N,N-di-lower alkylamino or pyrrolidino, or unsubstituted or substituted heteroaryl or heteroaralkyl; R 6 and R 7 simultaneously or independently of one another are hydrogen, lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, hydroxyalkoxy-lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, N-(hydroxy-lower al
  • These pharmaceutical preparations are those for enteral, in particular oral, and furthermore rectal, administration and those for parenteral administration to warm-blooded animals, especially to man, the pharmacological active ingredient being contained on its own or together with customary pharmaceutical adjuncts.
  • the pharmaceutical preparations contain (in percentages by weight), e.g., from approximately 0.001% to 100%, preferably from approximately 0.1% to approximately 100%, of the active ingredient.
  • compositions for enteral or parenteral administration are, e.g., those in unit dose forms, such as sugar-coated tablets, tablets, dispersible tablets, effervescent tablets, capsules, suspendable powders, suspensions or suppositories, or ampoules. These are prepared in a manner known per se, e.g. by means of conventional pan-coating, mixing, granulation or lyophilization processes.
  • Pharmaceutical preparations for oral administration can thus be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained and processing the mixture or granules, if desired or necessary, after addition of suitable adjuncts to give tablets or sugar-coated tablet cores.
  • Suitable carriers are, in particular, fillers such as sugars, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, furthermore binders, such as starch pastes, using, e.g., maize, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrants, such as the abovementioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphat
  • Adjuncts are primarily flow-regulating and lubricating agents, e.g. salicylic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Sugar-coated tablet cores are provided with suitable, if desired enteric, coatings, using, inter alia, concentrated sugar solutions which, if desired, contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enterc coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • Colorants or pigments e.g. for the identification or the marking of various doses of active ingredient, can be added to the tablets or sugar-coated tablet coatings.
  • Dispersible tablets are tablets which rapidly disintegrate in a comparatively small amount of liquid, e.g. water, and which, if desired, contain flavorings or substances for masking the taste of the active ingredient. They can advantageously be employed for the oral administration of large individual doses, in which the amount of active ingredient to be administered is so large that on administration as a tablet which is to be swallowed in undivided form or without chewing that it can no longer be conveniently ingested, in particular by children.
  • Further orally administrable pharmaceutical preparations are hard gelatin capsules and also soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The hard gelatin capsules can contain the active ingredient in the form of granules, e.g.
  • the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols, it also being possible to add stabilizers.
  • suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycols, it also being possible to add stabilizers.
  • suspendable powders e.g. those which are described as “powder in bottle”, abbreviated “PIB”, or ready-to-drink suspensions, are suitable for an oral administration form.
  • the active ingredient is mixed, e.g., with pharmaceutically acceptable surface-active substances, e.g., sodium lauryl sulfate or polysorbate, suspending auxiliaries, e.g. hydroxypropylcellulose, hydroxypropylmethylcellulose or another known from the prior art and previously described, e.g., in “Handbook of Pharmaceutical Ecipients”, pH regulators, such as citric or tartaric acid and their salts or a USP buffer and, if desired, fillers, e.g. lactose, and further auxiliaries, and dispensed into suitable vessels, advantageously single-dose bottles or ampoules.
  • a specific amount of water is added and the suspension is prepared by shaking. Alternatively, the water can also be added even before dispensing.
  • Rectally administrable pharmaceutical preparations are, e.g., suppositories which consist of a combination of the active ingredient with a suppository base.
  • a suitable suppository base is, e.g., natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • Gelatin rectal capsules can also be used which contain a combination of the active ingredient with a base substance.
  • Possible base substances are, e.g., liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
  • aqueous solutions of an active ingredient in water-soluble form are primarily suitable; furthermore suspensions of the active ingredient, such as appropriate oily injection suspensions, suitable lipophilic solvents or vehicles, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, being used, or aqueous injection suspensions which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, also stabilizers.
  • suitable lipophilic solvents or vehicles such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, being used, or aqueous injection suspensions which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran
  • the dosage of the active ingredient can depend on various factors, such as activity and duration of action of the active ingredient, severity of the illness to be treated or its symptoms, manner of administration, warm-blooded animal species, sex, age, weight and/or individual condition of the warm-blooded animal.
  • the doses to be administered daily in the case of oral administration are between 10 and approximately 120 mg/kg, in particular 20 and approximately 80 mg/kg, and for a warm-blooded animal having a body weight of approximately 40 kg, preferably between approximately 400 mg and approximately 4,800 mg, in particular approximately 800 mg to 3,200 mg, which is expediently divided into 2 to 12 individual doses.
  • the invention relates to novel preparations comprising at least one compound of the formula I in which
  • R 1 and R 5 simultaneously or independently of one another are hydrogen, halogen, hydroxyl, lower alkyl, halo-lower alkyl, lower alkoxy or halo-lower alkoxy;
  • R 2 and R 4 simultaneously or independently of one another are hydrogen or a radical which can be removed under physiological conditions, e.g.
  • R 3 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, R 6 R 7 N—C(O)-lower alkyl, substituted aryl, aryl-lower alkyl, substituted by N-lower alkylamino, N,N-di-lower alkylamino or pyrrolidino, or unsubstituted or substituted heteroaryl or heteroaralkyl; R 6 and R 7 simultaneously or independently of one another are hydrogen, lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, hydroxyalkoxy-lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, N-(hydroxy-lower alkyl)amino-lower alkyl, N,N-di
  • These pharmaceutical preparations are those for enteral, in particular oral, and furthermore rectal, administration, and those for parenteral administration to warm-blooded animals, especially to man, the pharmacological active ingredient being present on its own or together with customary pharmaceutical adjuncts.
  • the pharmaceutical preparations contain (in percentages by weight), e.g., from approximately 0.001% to 100%, preferably from approximately 0.1% to approximately 50%, of the active ingredient.
  • the present invention also makes available novel compounds of the general formula I
  • R 1 and R 5 simultaneously or independently of one another are hydrogen, halogen, lower-alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, carboxyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or nitrile;
  • R 2 and R 4 simultaneously or independently of one another are hydrogen, unsubstituted or substituted lower alkanoyl or aroyl, or a radical which can be removed under physiological conditions, e.g.
  • R 3 is R 6 R 7 N—C(O)-lower alkyl, unsubstituted or substituted aryl, aryl-lower alkyl, substituted by N-lower alkylamino, N,N-di-lower alkylamino or pyrrolidino, or unsubstituted or substituted heteroaryl or heteroaralkyl, with the proviso that R 3 is not phenyl or phenyl substituted by halogen, nitro, nitrile, hydroxyl, lower alkyl, halo-lower alkyl, lower alkoxy or lower alkoxycarbonyl if R 2 and R 4 are hydrogen, and R 1 and R 5 are hydrogen, halogen, lower alkyl, halo-lower alkyl, lower alkoXY or nitrile; R 6 and R 7 simultaneously or independently of one another are hydrogen, lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl
  • the invention relates to compounds of the formula I in which
  • R 1 and R 5 simultaneously or independently of one another are hydrogen, halogen, lower alkyl, halo-lower alkyl, lower alkoxy or halo-lower alkoxy;
  • R 2 and R 4 simultaneously or independently of one another are hydrogen or a radical which can be removed under physiological conditions, e.g.
  • R 3 is R 6 R 7 N—C(O)-lower alkyl, substituted aryl, aryl-lower alkyl, substituted by N-lower alkylamino, N,N-di-lower alkyl amino or pyrrolidino, or unsubstituted or substituted heteroaralkyl with the proviso that R 3 is not phenyl, substituted by halogen, nitro, nitrile, hydroxyl, lower alkyl, halo-lower alkyl, lower alkoxy or lower alkoxycarbonyl, if R 2 and R 4 are hydrogen and R 1 and R 5 are hydrogen, halogen, lower alkyl, halo-lower alkyl or lower alkoxy; R 6 and R 7 simultaneously or independently of one another are hydrogen, lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, hydroxyalkoxy-lower alkyl, amino-lower alkyl, N-low
  • the invention relates to compounds of the formula II in which
  • R 1 and R 5 simultaneously or independently of one another are hydrogen, halogen or lower alkyl;
  • R 2 and R 4 are hydrogen;
  • R 3 is R 6 R 7 N—C(O)-lower alkyl, substituted aryl, substituted by carboxyl or
  • R 8 R 9 N—C(O)-, aryl-lower alkyl, substituted by N-lower alkylamino, N,N-di-lower alkylamino or pyrrolidino, or unsubstituted or substituted heteroaralkyl;
  • R 6 and R 7 simultaneously or independently of one another are hydrogen, lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, hydroxyalkoxy-lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, N-(hydroxy-lower alkyl)amino
  • the invention relates especially to the specific compounds of the formula II and their salts, in particular their pharmaceutically acceptable salts, described in the examples.
  • the compounds can be prepared in a manner known per se by, e.g.,
  • R 3 is as defined above, or a salt thereof;
  • R 3 is as defined above, or a salt thereof;
  • R 1 , R 2 , R 4 and R 5 are as defined above, with a compound of the formula IV in which R 3 is as defined above, or a salt thereof;
  • R 1 -R 5 are as defined under the formulae II, III, IV, V and VI, if not stated otherwise.
  • the reaction according to process (a) corresponds to the ring rearrangement reaction of 1,2,4-dithiazolidines to 1,2,4-triazoles, with hydrazines, which is known per se [Wagner et al., Pharmazie 35:48-49 (1980)].
  • X ⁇ can be any desired anion, preferably a halogen anion, in particular a bromine anion.
  • the reaction can take place with or without solvents, advantageously it is carried out in a polar solvent or solvent mixture, in this case the compound IV can be present as such or alternatively as a solvate, in particular as a hydrate.
  • the reaction proceeds with cooling, at ambient temperature or elevated temperature up to the reflux temperature of the reaction mixture. It is preferably carried out at ambient temperature or elevated temperature.
  • the reaction according to process (b) corresponds to the reaction of benzoxazinones with hydrazines, which is known per se [Wagner et al., Z. Chem. 21:261 (1981) and Ryabukhin et al, Khim. Geterotsiklicheskikh Soed. (3), 406-410 (1983)].
  • the reaction is carried out in a polar solvent or solvent mixture, preferably in a lower alkanol, in particular methanol or ethanol, if desired with addition of a base, such as a tertiary amine, in particular tri-lower alkylamine, if the compound III and/or IV is present as a salt, e.g. as a hydrohalide.
  • the reaction proceeds with cooling, at ambient temperature or at elevated temperature up to the reflux temperature of the reaction mixture. In a particularly preferred embodiment, the reaction is carried out under reflux in ethanol.
  • the starting compounds V are accessible, e.g., by the reaction of appropriately substituted salicylic acid with appropriately substituted salicylamide in the presence of thionyl chloride (CH 388252 and Brunetti and Lüthi, Helv. Chim. Acta 55:1566 (1972)].
  • the starting compounds V can be prepared by heating a mixture of appropriately substituted salicyloyl chloride with suitably substituted salicylamide.
  • Process (c) corresponds to the reaction of diacylamines with hydrazines, which is known per se [Einhorn et al., Liebigs Ann. Chem. 343:229 (1905), Brunner, Ber. dtsch. chem. Ges. 47:2671 (1914) and Brunner, Mh. Chem. 36:509 (1915)].
  • the reaction takes place in polar, protic solvents under weak acid catalysis, preferably in aqueous acetic acid at elevated temperature.
  • the compounds of the formula II can also be prepared according to further processes which are known per se, e.g. according to the processes which are described by Temple, in: The Chemistry of Heterocyclic Compounds, Vol. 37, John Wiley & Sons, New York (1981).
  • Hydroxyl groups can be present, e.g., in the form of an easily cleavable ester or ether group, preferably of an alkanoyl or aralkanoyl ester group or of a cycloheteroalkyl, aralkyl or alkoxyalkyl ether group, but also of a silyl ester or silyl ether group, in particular as an acetyl or benzoyl ester or as a tetrahydropyranyl, benzyl or methoxymethyl ether.
  • an easily cleavable ester or ether group preferably of an alkanoyl or aralkanoyl ester group or of a cycloheteroalkyl, aralkyl or alkoxyalkyl ether group, but also of a silyl ester or silyl ether group, in particular as an acetyl or benzoyl ester or as a tetrahydropyranyl
  • the starting materials of the formulae III, IV, V and VI are novel in some cases and likewise a subject of the present invention. If necessary, suitable protective groups can be introduced or further derivatization can be carried out according to known methods.
  • the protective groups which are not a constituent of the desired final product of the formula II are removed in a manner known per se, e.g. by means of solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by means of reduction, optionally stepwise or simultaneously.
  • starting compounds of the formula I or any intermediates contain interfering reactive groups, e.g. carboxyl, hydroxyl or amino groups, these can be temporarily protected by easily removable protective groups.
  • customary processes are used, e.g. solvolysis of excess reagents; recrystal-lization, chromatography, e.g. partition, ion or gel chromatography, partition between an in-organic and organic solvent phase; single or multiple extraction, in particular after acidification or increasing the basicity or the salt content, drying over hygroscopic salts or at elevated temperature, if desired with passing through or passing by of a gas stream; digestion; filtration; washing; dissolution; evaporation (if necessary in a vacuum or high vacuum); distillation; precipitation; centrifugation; crystallization, e.g. of compounds obtained in oil form or from the mother liquor, it also being possible to seed the final product with a crystal; lyophilization; or a combination of two or more of the working-up steps mentioned, which can also be employed repeatedly; etc.
  • chromatography e.g. partition, ion or gel chromatography, partition between an in-organic and organic solvent phase
  • single or multiple extraction in particular after acid
  • Starting materials and intermediates can be used in pure form, e.g. after working up, as last-mentioned, in partially purified form or alternatively, e.g., directly as crude products.
  • the compounds, including their salts, can also be obtained in the form of hydrates or solvates, or their crystals can include, e.g., the solvent used for crystallization.
  • Solvents and diluents are, e.g., water, alcohols, e.g. lower alkanols, such as methanol, ethanol, propanol, butanol or ethylene glycol monomethyl ether (methylcellosolve), diols, such as ethylene glycol, tri- or polyols, such as glycerol or diethylene glycol, or aryl alcohols, such as phenol or benzyl alcohol, acid amides, e.g. carboxamides, such as N,N-dimethylformamide, or N,N-dimethylacetamide, amides of inorganic acids, such as hexamethylphosphoramide, ethers, e.g.
  • alcohols e.g. lower alkanols, such as methanol, ethanol, propanol, butanol or ethylene glycol monomethyl ether (methylcellosolve)
  • diols such as ethylene glycol, tri- or
  • cyclic ethers such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons, such as halo-lower alkanes, e.g. methylene chloride or chloroform, ketones, such as acetone, nitrites, such as acetonitrile, esters, such as ethyl acetate, bisalkane sulfoxides, such as dimethyl sulfoxide, nitrogen heterocycles, such as N-methylpyrrolidone or pyridine, hydrocarbons, e.g.
  • those starting substances and intermediates in each case in free form or in salt form, are preferably used which lead to the compounds II or their salts described as particularly valuable at the outset.
  • Novel starting substances and intermediates, in each case in free form or in salt form, for the preparation of the compounds II or their salts, their use and processes for their preparation also form a subject of the invention.
  • the invention also relates to those embodiments of the process in which a compound obtainable in any desired process stage as an intermediate is used as a starting material and the missing process steps are carried out, or in which a starting substance is formed under the reaction conditions or is used in the form of a derivative, e.g. of a salt thereof.
  • Salts of compounds II can be prepared in a manner known per se.
  • acid addition salts, e.g., of compounds II are obtained by treatment with a suitable acid or a suitable ion-exchange reagent and salts with bases are obtained by treatment with a suitable base or a suitable ion-exchange reagent.
  • Salts of compounds of the formula II can be converted in a customary manner into the free compounds II; acid addition salts can be converted, e.g., by treatment with a suitable basic agent or a suitable ion-exchange reagent; and salts with bases can be converted, e.g., by treatment with a suitable acid or a suitable ion-exchange reagent.
  • Salts of compounds II can be converted into other salts of compounds II in a manner known per se; acid addition salts can be converted, e.g., into other acid addition salts, e.g. by treatment of a salt of an inorganic acid, such as a hydrochloride, with a suitable metal salt, such as a sodium, barium or silver salt, of another acid, e.g. silver acetate, in a suitable solvent, in which an inorganic salt formed, e.g. silver chloride, is insoluble and thus precipitates from the reaction mixture.
  • a salt of an inorganic acid such as a hydrochloride
  • a suitable metal salt such as a sodium, barium or silver salt
  • an inorganic salt formed e.g. silver chloride
  • the compounds II with salt-forming properties can be obtained in free form or in the form of salts.
  • the compounds II including their salts of salt-forming compounds can also be obtained in the form of their hydrates and/or include other solvents, e.g., if appropriate, solvents used for the crystallization of compounds present in solid form.
  • the compounds II and their salts can be present in the form of one of the possible isomers, e.g. stereoisomers or tautomers, or as a mixture thereof.
  • pure isomers obtainable are, e.g., pure enantiomers, pure diastereoisomers or pure tautomers.
  • isomer mixtures which can be present are, e.g., racemates or diastereoisomer mixtures.
  • Isomer mixtures of compounds II in free form or in salt form obtainable according to the process or in other ways can be separated into the components in a customary manner, e.g. on the basis of the physicochemical differences of the constituents, in a known manner by fractional crystallization, distillation and/or chromatography.
  • the more active isomer is isolated.
  • the starting material can be prepared, e.g., as follows:
  • the starting material can be prepared, e.g., as follows:
  • Example 2 0.6 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) is dissolved in 20 ml of methanol with 0.4 g of sodium hydroxide and the mixture is stirred at room temperature for 2 h. It is acidified with 0.1 N hydrochloric acid and the precipitated crystals are filtered off. After washing with water and drying, [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetic acid remains as colorless crystals of m.p. 231-233° C.
  • Example 2 2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) are dissolved in15 ml of ethanol and treated with 0.8 ml of 8 M methylamine in ethanol. The mixture is stirred at 60° C. for 3 h and then cooled. The crystals precipitating in the course of this are filtered off and washed with ethanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-methylacetamide remains as colorless crystals m.p. 247-249° C.
  • Example 2 2.0 g of ethyl 13,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) are dissolved in 10 ml of ethanolamine and stirred at room temperature for 2 h. The mixture is concentrated to dryness in vacuo and the residue is crystallized from isopropanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-hydroxyethyl)acetamide remains as colorless crystals of m.p. 208-211° C.
  • Example 2 4.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) are dissolved in 30 ml of 2-methoxyethylamine and the mixture is stirred at room temperature for 2 h. It is concentrated to dryness in vacuo and the residue is crystallized from isopropanol. After drying, 2-[3,5-Bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-methoxyethyl)acetamide remains as colorless crystals of m.p. 184-186° C.
  • N- ⁇ 2-[bis(2-hydroxyethyl)amino]ethyl ⁇ -2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetamide remains as a colorless foam.
  • Example 2 2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) are dissolved in 15 ml of ethanolic dimethylamine (33 per cent) and the solution is stirred at 60° C. for 20 h. The crystals precipitating on cooling are recrystallized from isopropanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N,N-dimethylacetamide remains as colorless crystals of m.p. 196-197° C.
  • Example 2 2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 9 ml of N,N,N′-trimethylethylenediamine are stirred at 80° C. for 5 h. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol.
  • active ingredient is below to be understood as meaning a compound of the formula I, in free form or in the form of a pharmaceutically acceptable salt, in particular a compound of the type which is described as a product in one of the above examples.
  • Tablets comprising 200 mg of active ingredient each, can be prepared as follows:
  • composition 10,000 tablets
  • the active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, the magnesium stearate, the talc and the silica is admixed and the mixture is compressed to give tablets of weight 295.0 mg each and 200 mg active ingredient content, which, if desired, can be provided with breaking notches for finer adjustment of the dosage.
  • Coated tablets each comprising 400 mg of active ingredient, can be prepared as follows.
  • Active ingredient 400.0 g Lactose 100.0 g Maize starch 70.0 g Talc 8.5 g Calcium stearate 1.5 g Hydroxypropylmethylcellulose 2.36 g Shellac 0.64 g Water q.s. Dichloromethane q.s.
  • the active ingredient, the lactose and 40 g of the maize starch are mixed and moistened and granulated with a paste prepared from 15 g of maize starch and water (with warming).
  • the granules are dried, and the remainder of the maize starch, the talc and the calcium stearate is added and mixed with the granules.
  • the mixture is compressed to give tablets and these are coated with a solution of hydroxypropylmethylcellulose and shellac in dichloromethane; final weight of the coated tablet: 583 mg.
  • Hard gelatin capsules comprising 500 mg of active ingredient, can be prepared, e.g., in the following manner:
  • Composition for 1,000 capsules
  • the sodium lauryl sulfate is sieved into the lyophilized active ingredient through a sieve having a mesh width of 0.2 mm. Both components are intimately mixed. Then the lactose is first sieved in through a sieve having a mesh width of 0.6 mm and the microcrystalline cellulose is then sieved in through a sieve having a mesh width of 0.9 mm. After that, the ingredients are again intimately mixed for 10 minutes. Finally, the magnesium stearate is sieved in through a sieve having a mesh width of 0.8 mm. After 3 minutes' further mixing, 790 mg each of the formulation obtained are dispensed into hard gelatin capsules of suitable size.
  • Oral suspension powder comprising 300 mg of active ingredient, can be prepared, eg., as follows
  • Composition (1 administration): Active ingredient 300 mg Hydroxypropylcellulose (Klucel HF) 50 mg Tartaric acid 100 mg Sodium lauryl sulfate 100 mg
  • the sodium lauryl sulfate is sieved into the lyophilized active ingredient through a sieve having a mesh width of 0.2 mm. Both components are intimately mixed. Then the microcrystalline cellulose is sieved in through a sieve having a mesh width of 0.9 mm. After this, the ingredients are again intimately mixed for 10 minutes. Finally, the tartaric acid is sieved in through a sieve having a mesh width of 0.8 mm. After 3 minutes' further mixing, the mixture is dispensed into a container having a capacity of at least 10 ml. For use, the mixture is made up to 10 ml with water and vigorously shaken.
  • Test I Iron excretion induced by compounds of formula I or II [method as described in Bergeron et al., J. Med. Chem. 34:2072-2078 (1991)]
  • mice Male Sprague-Dawley rats averaging 400 g are housed in Nalgene plastic metabolic cages and are given free access to water. The animals are anesthetized with sodium pentobarbital (50 mg/kg), given ip.
  • the bile duct is cannulated with 22 gauge PE 50 tubing which is inserted ca. 2 cm into the duct and tied firmly in place.
  • a skin-tunneling needle is inserted from the shoulder area around the abdominal incision. The cannula is threaded through the needle until it emerges from the shoulder opening. The cannula is then passed from the animal to the swivel inside a metal torque-transmitting tether, which is attached to a rodent jacket.
  • the cannula is directed from the animal to a Gilson microfraction collector by a fluid swivel mounted above the metabolic cage. This system allows the animal to move freely in the cage while continuous bile samples are being collected. Bile samples are collected in plastic disposable tubes at 3 h intervals for 24 h. Urine samples are collected in plastic disposable tubes for 24 h.
  • Compounds of formula I or II are prepared in 60% water, 40% Cremophor RH-40 (v/v). All animals are fasted for 48 h before the administration of the compound of formula I or II and the fast is maintained throughout the course of the experiment.
  • the iron indicator solution, solution A is prepared by diluting a stock aqueous solution of 0.134 mM mercaptoacetic acid and 1.9 mM bathophenanthrolinedisulfonic acid disodium salt with 5 parts water and 5 parts saturated aqueous sodium acetate.
  • Solution B is prepared as above but without the bathophenanthroline.
  • An equal volume of a 10% trichloroacetic acid solution in 3 M HCl (solution C) is added to a urine sample (2.5 ml), and the sample heated in a 65° C. bath for 4 h. After filtration through nylon filters, two 1 ml aliquots are removed.
  • Solution A (5 ml) is added to the sample, and solution B (5 ml) is added to the blank.
  • Bile samples are prepared as the urine samples; however, the volumes are reduced. Standard iron curves are generated with each assay. All samples are transferred to polystyrene cuvettes and the absorbance measured at 535 nm. Compounds of formula I or II are effective in this assay when administered at a dose in the range of from 10 to 200 mg/kg, e.g. 100 to 150 mg/kg. The induced total iron excretion is in the range of about 10 to 1500 ⁇ g Fe/kg body weight, e.g. 90 to 1000 ⁇ g Fe/kg body weight.
  • Test II Iron excretion induced by compounds of formula I or II [method as described in Bergeron et al., Blood 81:2166-2173 (1993)]
  • the animals are iron-overloaded by 3 i.p. injections of iron (III) hydroxide polyisomaltose (Anaemex, Ciba-Geigy, Basel, Switzerland) at 14-day intervals (200 mg/kg twice and 100 mg/kg at the third injection). Prior to the first exposure to an iron chelator, the marmosets are rested at least 8 weeks.
  • test compounds are dispersed in 40% aqueous Cremophor RH 40 (BASF, Ludwigshafen, Germany) for administration.
  • the applied volume is 5 ml/kg body weight.
  • the monkeys receive a low-iron diet 7 days before and throughout the experiments (4 days).
  • the diet is prepared by mixing 628.9 g of a liquid diet for primates (Nafag No. 9694), 83 g of the corresponding lipid mixture (Nafag No. 9696), 131.3 g dietary fiber (Sanacell, Nafag) and 1.0 L of distilled water.
  • Each monkey receives 30 g of this liquid diet, mixed with 20 g milk rice per day.
  • the iron content of this food mixture is 3.1 mg per kg.
  • the animals are placed into acrylic glass metabolic cages especially designed for marmosets (square area of 0.2 m 2 and 55 cm high), 48 hours prior to drug administration.
  • Marmosets live in pairs or families and react to separation from their mate. To keep the separation stress at a minimum, usually all animals from a family participate in the same experiment. By placing the animals from a social unit into adjacent metabolic cages, the animals, although separated, can see each other. Urine and feces are collected in 24-hour fractions to determine background iron excretion. After p.o. administration of the chelator, the marmosets are maintained in the same metabolic cage for another 48 hours. Urine and feces are collected in 24 hour fractions. Thus, each animal serves as its own control.
  • Urinary iron concentration is determined calorimetrically using the bathophenanthroline method [Smith et al., Analyst 77:418-422 (1952)]. Two 100 ⁇ l aliquots of each sample are placed into separate wells of a conical-bottom 96-well plate. To each well 100 ⁇ l of a 10% trichloroacetic acid solution in 3M HCl are added. After incubation at 65° C. for 4 h, the plate is centrifuged for 10 minutes at 1,300 ⁇ g. A 100 ⁇ l aliquot of each supernatant is transferred into the corresponding well of a flat-bottom 96-well plate.
  • the iron indicator solution (6.32 ml water, 80 ⁇ l mercaptoacetic acid, 12.4 mg bathophenanthroline-disulfonic acid disodium salt, 3.16 ml saturated sodium acetate and 4.22 ml NaOH 5.9N) and blank solution (same but without bathophenanthroline) are added to the first and second aliquot of each sample, respectively.
  • the plate is agitated and the absorbance is measured after 30 min at 535 nm with a microplate reader (UVmax, Molecular Devices).
  • the iron concentration of each sample is calculated using a standard curve (0 to 20 ⁇ g/ml) after subtraction of the individual blank.
  • Fecal iron in each sample is determined by flame atomic absorption spectrometry after wet-ashing the entire (24-hour) sample of feces. All results are expressed as gg iron excreted per kg body weight. For the calculation of chelator-induced iron excretion, the mean pretreatment values of each animal are subtracted from the posttreatment values.
  • Compounds of formula I or II are effective in this assay when administered at a dose in the range from 10 to 200 mg/kg, e.g. 20 to 150 mg/kg.
  • the induced total iron excretion is in the range of about 10 to 3000 ⁇ g Fe/kg body weight, e.g. 20 to 2500 ⁇ g Fe/kg body weight.

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US20050008699A1 (en) * 2003-07-11 2005-01-13 Fred Wehling Effervescent glucosamine composition
US20050080120A1 (en) * 2001-11-06 2005-04-14 Rene Lattmann 4-[3,5-bis-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid derivatives for treating an excess of metal in the body
WO2005058320A1 (en) * 2003-12-19 2005-06-30 Novartis Ag COMBINATION OF (a) N-{5-[4-(4-METHYL-PIPERAZINO-METHYL)-BENZOYLAMIDO]-2METHYLPHENYL}-4-(3-PYRIDYL)-2-PYRIMIDINE-AMINE AND (b) AT LEAST ONE HYPUSINATION INHIBITOR AND THE USE THEREOF
WO2006084683A1 (en) * 2005-02-10 2006-08-17 Novartis Ag Methods for improving drug disposition
US20080114001A1 (en) * 2005-01-28 2008-05-15 Manley Paul W Use of Pyrimidylaminobenzamides for the Treatment of Diseases that Respond to Modulation of Tie-2 Kinase Activity
US20080199428A1 (en) * 2005-05-31 2008-08-21 Alberti Daniele M Treatment of Liver Diseases in Which Iron Plays a Role in Pathogenesis
US20090082412A1 (en) * 2007-09-26 2009-03-26 Protia, Llc Deuterium-enriched deferasirox
JP2009513688A (ja) * 2005-11-01 2009-04-02 ノバルティス アクチエンゲゼルシャフト シンチグラフィー法
US20090111863A1 (en) * 2007-10-31 2009-04-30 Esposito Luke A Compounds, Compositions and Methods for the Treatment of Beta-Amyloid Diseases and Synucleinopathies
WO2009147529A1 (en) * 2008-06-02 2009-12-10 Actavis Group Ptc Ehf Substantially pure deferasirox and processes for the preparation thereof
US20090317489A1 (en) * 2006-05-09 2009-12-24 Hanspeter Nick Combination Comprising an Iron Chelator and an Anti-Neoplastic Agent and Use Thereof
WO2009130604A3 (en) * 2008-04-21 2009-12-30 Actavis Group Ptc Ehf Solid state forms of deferasirox salts and process for the preparation thereof
US20100129434A1 (en) * 2006-07-13 2010-05-27 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Compositions and methods for the treatment of mucormycosis and other fungal diseases
US20100285024A1 (en) * 2009-03-19 2010-11-11 Ibrahim Ashraf S Vaccine compositions and methods for treatment of mucormycosis and other fungal diseases
EP2253317A2 (en) 2007-05-22 2010-11-24 Novartis AG Triazol compounds for treating biofilm formation
EP2255805A1 (en) 2006-05-23 2010-12-01 Novartis AG Deferasirox for the treatment of hereditary hemochromatosis
WO2011070560A1 (en) 2009-12-07 2011-06-16 Mapi Pharma Hk Limited Processes for the preparation of deferasirox, and deferasirox polymorphs
WO2012025935A2 (en) 2010-08-25 2012-03-01 Ramamohan Rao Davuluri A process for the preparation of 2-(2-hydroxyphenyl)-benz[1,3]oxazin-4-one and its use for preparation of 4-[3, 5-bis (2-hydroxyphenyl)-1h-1, 2, 4-triazol-1-yl] benzoic acid
WO2012069946A1 (en) 2010-11-24 2012-05-31 Alembic Pharmaceuticals Limited Process for the preparation of deferasirox
US20130267572A1 (en) * 2006-11-29 2013-10-10 Novartis Ag Plymorphic Forms of Deferasirox (ICL670A)
US8563590B2 (en) 2008-03-05 2013-10-22 Proteotech, Inc. Compounds, compositions and methods for the treatment of islet amyloid polypeptide (IAPP) accumulation in diabetes
CN103454370A (zh) * 2013-09-11 2013-12-18 中美华世通生物医药科技（武汉）有限公司 一种利用hplc测定原料药中苯肼类化合物残留的方法
AU2014224252B2 (en) * 2013-03-06 2016-09-22 Biocon Limited Process for the preparation of Deferasirox
WO2016203488A1 (en) * 2015-06-16 2016-12-22 Havaldar Freddy H Preparation of novel deferasirox analogues for antimalarial activity
WO2017158559A1 (en) 2016-03-17 2017-09-21 Lupin Limited Compositions of deferasirox
US9796605B2 (en) 2011-01-14 2017-10-24 Disease Adsorption System Technologies Co., Ltd. Polymeric iron chelating agent
US10751304B2 (en) 2008-10-10 2020-08-25 The Board Of Trustees Of The Leland Stanford Junior University Topical and transdermal delivery of HIF-1 modulators to prevent and treat chronic wounds
US11331288B2 (en) 2017-09-14 2022-05-17 The Board Of Trustees Of The Leland Stanford Junior University Conditioning irradiated tissue for increasing vascularity

Families Citing this family (81)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6677487B2 (en) 2001-08-30 2004-01-13 Pharmacia Corporation α-haloenamine reagents
ES2192494B1 (es) * 2002-03-27 2005-02-16 Consejo Superior De Investigaciones Cientificas Derivados de 1,2,4-triazol con propiedades cannabinoides.
GB0223978D0 (en) * 2002-10-15 2002-11-20 Novartis Ag Organic compound
MY142651A (en) * 2003-03-18 2010-12-15 Merck Sharp & Dohme Biaryl substituted triazoles as sodium channel blockers
BRPI0416319A (pt) * 2003-11-10 2007-01-09 Merck & Co Inc composto, composição farmacêutica, métodos de tratamento ou prevenção da dor, das sìndromes, e de doença, e, métodos de administrar anestesia local, e para a neuroproteção sob condições isquêmicas
GB0408078D0 (en) * 2004-04-08 2004-05-12 Novartis Ag Organic compounds
US9737511B2 (en) * 2004-05-24 2017-08-22 Geoffrey C. GURTNER Method of treating or preventing pathologic effects of acute increases in hyperglycemia and/or acute increases of free fatty acid flux
JP2008500347A (ja) * 2004-05-24 2008-01-10 ニュー・ヨーク・ユニヴァーシティー 高血糖症による血糖の急激な増加及び／又は急激な遊離脂肪酸流動の増加の病理学的影響の治療方法又は予防方法
AU2006303514B2 (en) * 2005-10-19 2010-06-24 Novartis Ag Dispersible tablets comprising deferasirox
ES2458615T3 (es) * 2006-02-03 2014-05-06 Taisho Pharmaceutical Co., Ltd. Derivado de triazol
EP2049108A1 (en) * 2006-08-04 2009-04-22 Novartis AG Treatment of endocrine dysfunction using iron chelators
RU2339625C2 (ru) * 2006-11-02 2008-11-27 Российский химико-технологический университет (РХТУ им. Д.И. Менделеева) ЗАМЕЩЕННЫЕ N-[ω-АЗОЛ-1-ИЛ)АЛКИЛ]БЕНЗОЛСУЛЬФАМИДЫ В КАЧЕСТВЕ СРЕДСТВ С АНТИАГРЕГАЦИОННОЙ АКТИВНОСТЬЮ И СПОСОБЫ ИХ ПОЛУЧЕНИЯ
EP1927591A1 (en) * 2006-11-29 2008-06-04 Novartis AG Polymorphic Forms of Deferasirox (ICL670)
EP2108013A2 (en) * 2007-01-29 2009-10-14 Teva Gyógyszergyár Zártköruen Muködo Részvénytársaság Crystalline forms of deferasirox
AU2008250041A1 (en) * 2007-05-14 2008-11-20 Novartis Ag Use of iron chelator for the treatment of myocardial infarction
WO2009016359A1 (en) * 2007-07-27 2009-02-05 Pliva Hrvatska D.O.O. New forms of deferasirox
EP2062572A1 (en) 2007-11-19 2009-05-27 Teva Pharmaceutical Industries Ltd. Pharmaceutical compositions
CZ301873B6 (cs) * 2008-01-30 2010-07-14 Farmak, A. S. Zpusob prípravy kyseliny 4-[3,5-bis(2-hydroxyfenyl)-[1,2,4]triazol-1-yl]benzoové
WO2009106824A2 (en) * 2008-02-25 2009-09-03 Cipla Limited Pharmaceutical formulations
TWI488624B (zh) 2008-09-22 2015-06-21 Nat University Corp Asahikawa Medical College 鐵螯合劑、其製造方法及鐵離子之定量、捕捉方法
WO2010092419A1 (en) 2009-02-12 2010-08-19 Assistance Publique - Hopitaux De Paris Combined treatment of multiple sclerosis
IT1398770B1 (it) * 2009-07-22 2013-03-18 Bellacchio Oligonucleotidi attivabili mediante l'appaiamento con sequenze di acidi nucleici e loro uso
WO2011021218A2 (en) * 2009-08-12 2011-02-24 Msn Laboratories Limited Process for the preparation of 4-[3,5-bis(2-hydroxyphenyl)-1h-1,2,4-triazol-1-yl]-benzoic acid and its amine salts
KR20130041144A (ko) 2010-07-08 2013-04-24 라티오팜 게엠베하 데페라시록스의 경구투여용 제제
PE20140166A1 (es) * 2010-10-01 2014-02-17 Cipla Ltd Composicion farmaceutica que comprende deferasirox
US20140276107A1 (en) 2011-10-14 2014-09-18 Photocure Asa Photodynamic diagnosis
EP2779956A1 (en) 2011-10-14 2014-09-24 Photocure ASA Stent
US8822464B2 (en) 2011-11-28 2014-09-02 Boehringer Ingelheim International Gmbh N-aryl-piperazine derivatives and their use as positive allosteric modulators of mGluR5 receptors
US8741892B2 (en) 2011-12-05 2014-06-03 Boehringer Ingelheim International Gmbh Compounds
US8642774B2 (en) 2011-12-08 2014-02-04 Boehringer Ingelheim International Gmbh Compounds
US8796467B2 (en) 2011-12-13 2014-08-05 Boehringer Ingelheim International Gmbh Compounds
US8846948B2 (en) 2011-12-13 2014-09-30 Boehringer Ingelheim International Gmbh Compounds
US8937176B2 (en) 2011-12-14 2015-01-20 Boehringer Ingelheim International Gmbh Compounds
US8716277B2 (en) 2011-12-14 2014-05-06 Boehringer Ingelheim International Gmbh Substituted imidazole compounds useful as positive allosteric modulators of mGlu5 receptor activity
US8883789B2 (en) 2011-12-14 2014-11-11 Boehringer Ingelheim International Gmbh Piperazine derivatives and their use as positive allosteric modulators of mGluR5 receptors
US8889677B2 (en) * 2012-01-17 2014-11-18 Boehringer Ingellheim International GmbH Substituted triazoles useful as mGlu5 receptor modulators
PT2964202T (pt) * 2013-03-08 2019-02-06 Novartis Ag Formulações orais de deferasirox
CA2911671A1 (en) * 2013-05-10 2014-11-13 Cipla Limited Low dose pharmaceutical composition
DE102013217390A1 (de) 2013-09-02 2015-03-05 Henkel Ag & Co. Kgaa Wasch- und Reinigungsmittel mit verbesserter Leistung
JOP20200094A1 (ar) 2014-01-24 2017-06-16 Dana Farber Cancer Inst Inc جزيئات جسم مضاد لـ pd-1 واستخداماتها
JOP20200096A1 (ar) 2014-01-31 2017-06-16 Children’S Medical Center Corp جزيئات جسم مضاد لـ tim-3 واستخداماتها
WO2015138920A1 (en) 2014-03-14 2015-09-17 Novartis Ag Antibody molecules to lag-3 and uses thereof
ES2734675T3 (es) 2014-05-20 2019-12-11 Sanovel Ilac Sanayi Ve Ticaret As Formulación de comprimido dispersable en agua que contiene deferasirox
EP2987482A1 (en) 2014-08-22 2016-02-24 Santa Farma Ilaç Sanayi A.S. Soluble and dispersible pharamaceutical deferasirox formulation
MA41044A (fr) 2014-10-08 2017-08-15 Novartis Ag Compositions et procédés d'utilisation pour une réponse immunitaire accrue et traitement contre le cancer
AU2015333687B2 (en) 2014-10-14 2021-03-18 Dana-Farber Cancer Institute, Inc. Antibody molecules to PD-L1 and uses thereof
WO2016100882A1 (en) 2014-12-19 2016-06-23 Novartis Ag Combination therapies
KR20160088965A (ko) 2015-01-16 2016-07-27 대원제약주식회사 데페라시록스를 함유하는 현탁제
MY190404A (en) 2015-03-10 2022-04-21 Aduro Biotech Inc Compositions and methods for activating "stimulator of interferon gene"-dependent signalling
CN104817538A (zh) * 2015-03-13 2015-08-05 东南大学 去铁斯诺-他克林金属离子鳌合剂及其药物用途
WO2016167729A1 (en) 2015-04-16 2016-10-20 Öğün Yusuf Toktamiş Dispersible tablets comprising deferasirox
EP3095443A1 (en) 2015-05-21 2016-11-23 Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. Pharmaceutical composition comprising deferasirox
EP3328418A1 (en) 2015-07-29 2018-06-06 Novartis AG Combination therapies comprising antibody molecules to pd-1
PT3317301T (pt) 2015-07-29 2021-07-09 Novartis Ag Terapias de associação compreendendo moléculas de anticorpo contra lag-3
EP3878465A1 (en) 2015-07-29 2021-09-15 Novartis AG Combination therapies comprising antibody molecules to tim-3
KR101695970B1 (ko) 2015-07-31 2017-01-13 건일제약 주식회사 데페라시록스 함유 산제 및 그 제조방법
CN106554770B (zh) * 2015-09-29 2018-10-19 杭州杜易科技有限公司 一种三唑衍生物金属离子荧光探针及其制备方法和应用
PE20181496A1 (es) 2015-10-23 2018-09-18 Vifor Int Ag Inhibidores de ferroportina novedosos
JP2019503349A (ja) 2015-12-17 2019-02-07 ノバルティス アーゲー Ｐｄ−１に対する抗体分子およびその使用
US11098077B2 (en) 2016-07-05 2021-08-24 Chinook Therapeutics, Inc. Locked nucleic acid cyclic dinucleotide compounds and uses thereof
EP3518904A1 (en) 2016-09-30 2019-08-07 Synthon B.V. Pharmaceutical composition comprising deferasirox
JOP20180036A1 (ar) 2017-04-18 2019-01-30 Vifor Int Ag أملاح لمثبطات فروبورتين جديدة
UY37695A (es) 2017-04-28 2018-11-30 Novartis Ag Compuesto dinucleótido cíclico bis 2’-5’-rr-(3’f-a)(3’f-a) y usos del mismo
CZ2017255A3 (cs) 2017-05-04 2018-11-14 Zentiva, K.S. Filmem potažené tablety Deferasiroxu
WO2018208242A1 (en) 2017-05-10 2018-11-15 İlko Ilaç Sanayi Ve Ticaret Anonim Şirketi Formulation of deferasirox tablet for oral suspension composition with better processability
EP3642240A1 (en) 2017-06-22 2020-04-29 Novartis AG Antibody molecules to cd73 and uses thereof
EP3489692A1 (de) 2017-11-28 2019-05-29 Siemens Healthcare Diagnostics Products GmbH Prothrombinzeit-reagenz enthaltend einen eisenchelator
TR201722910A2 (tr) 2017-12-29 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Deferasi̇roks i̇çeren suda dağilabi̇len tablet formülasyonlari
KR20190110771A (ko) 2018-03-21 2019-10-01 주식회사 한국팜비오 데페라시록스를 함유하는 소형 분산성 정제
CN108727287B (zh) * 2018-05-10 2020-10-27 东南大学 1,2,4-三唑类化合物及其盐和应用
UY38247A (es) 2018-05-30 2019-12-31 Novartis Ag Anticuerpos frente a entpd2, terapias de combinación y métodos de uso de los anticuerpos y las terapias de combinación
GR1009592B (el) * 2018-07-03 2019-09-11 Φαρματεν Α.Β.Ε.Ε. Φαρμακευτικο σκευασμα που περιλαμβανει εναν χηλικο παραγοντα συμπλεκτικο του σιδηρου και μεθοδος για την παρασκευη αυτου
KR20200113116A (ko) 2019-03-22 2020-10-06 주식회사 한국팜비오 데페라시록스를 포함하는 필름코팅정제
TW202102478A (zh) 2019-04-01 2021-01-16 瑞士商威佛（國際）股份有限公司 新穎的鐵螯合物
CN114502590A (zh) 2019-09-18 2022-05-13 诺华股份有限公司 Entpd2抗体、组合疗法、以及使用这些抗体和组合疗法的方法
IT202000000922A1 (it) 2020-01-20 2021-07-20 Cage Chemicals S R L Complessi di ferro e relativi sali come agenti di contrasto per MRI
US11155547B1 (en) * 2020-06-18 2021-10-26 Alterity Therapeutics Limited Compounds for and methods of treating diseases
WO2022186809A1 (en) 2021-03-05 2022-09-09 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi The film coated tablet comprising deferasirox
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CN114478410B (zh) * 2022-03-31 2022-11-29 中山大学 一种二取代苯基-1,2,4-三氮唑衍生物及其制备和应用
CN114591254B (zh) * 2022-03-31 2023-10-13 中山大学 一种3,5-二取代苯基-1,2,4-三氮唑衍生物及其制备方法和应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1018987A (en) 1963-01-24 1966-02-02 Geigy Ag J R Improvements relating to ú´-hydroxyphenyl-ú¾-triazines and their use
GB1528564A (en) 1976-06-23 1978-10-11 Bayer Ag Fungicidal and nematicidal agents
US4528196A (en) 1981-02-23 1985-07-09 The United States Of America As Represented By The Department Of Health And Human Services Chelating agents for the treatment of iron overload
EP0185401A1 (en) 1984-11-20 1986-06-25 Shell Internationale Researchmaatschappij B.V. Heterocyclic herbicides
EP0315434A2 (en) 1987-11-02 1989-05-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Pyridoxal hydrazone derivatives their production and use and pharmaceutical compositions containing the same
EP0480659A2 (en) 1990-10-08 1992-04-15 Merck & Co. Inc. Use of Angiotensin-II antagonists for the manufacture of a medicament for the treatment of hyperuricemia
DE4320801A1 (de) 1993-06-23 1995-01-05 Fahlberg List Pharma Gmbh 2-Hydroxyphenylsubstituierte 1,2,4-Triazole und 1,2,4-Oxadiazole, ihre Verwendung als pharmazeutische Wirkstoffe und sie enthaltende Arzneimittel

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1280851A1 (ru) * 1983-07-08 1996-05-27 Ростовский государственный университет 1-фенил-3-алкил-5-(o-оксифенил)-1,2,4-триазолы, обладающие транквилизирующим и антигипоксическим действием, и 1-фенил-3-н-бутил-5-(о-оксифенил)-1,2,4-триазол, обладающий транквилизирующим, антигипоксическим и анальгетическим действием

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1018987A (en) 1963-01-24 1966-02-02 Geigy Ag J R Improvements relating to ú´-hydroxyphenyl-ú¾-triazines and their use
GB1528564A (en) 1976-06-23 1978-10-11 Bayer Ag Fungicidal and nematicidal agents
US4528196A (en) 1981-02-23 1985-07-09 The United States Of America As Represented By The Department Of Health And Human Services Chelating agents for the treatment of iron overload
EP0185401A1 (en) 1984-11-20 1986-06-25 Shell Internationale Researchmaatschappij B.V. Heterocyclic herbicides
EP0315434A2 (en) 1987-11-02 1989-05-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Pyridoxal hydrazone derivatives their production and use and pharmaceutical compositions containing the same
EP0480659A2 (en) 1990-10-08 1992-04-15 Merck & Co. Inc. Use of Angiotensin-II antagonists for the manufacture of a medicament for the treatment of hyperuricemia
DE4320801A1 (de) 1993-06-23 1995-01-05 Fahlberg List Pharma Gmbh 2-Hydroxyphenylsubstituierte 1,2,4-Triazole und 1,2,4-Oxadiazole, ihre Verwendung als pharmazeutische Wirkstoffe und sie enthaltende Arzneimittel

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
Bergeron, et al., Blood, Vol. 81, No. 8, pp. 2166-2173 (1993).
Bergeron, et al., J. Med. Chem., Vol. 34, pp. 2072-2078 (1991).
Bickel, et al., Helv. Chim. Acta, Vol. 46, pp. 1385-1389 (1963).
Brunetti, et al., Helv. Chim. Acta, vol. 55, pp. 1566-1595 (1972).
Brunner K., Ber. dtsch. chem. Ges., vol. 47, pp. 2671-2680 (1914).
Brunner K., Mh Chem., vol. 36, pp. 509-534 (1915).
Chemical Abstracts, vol. 122: 306557 (1995).
Chemical Abstracts, vol. 60: 9528g (1964).
Chemical Abstracts, vol. 77: 10154w (1972).
Chemical Abstracts, vol. 9: 210 (1915).
Chemical Abstracts, vol. 9: 3058 (1915).
Chemical Abstracts, vol. 93: 95196a (1980).
Chemical Abstracts, vol. 95: 18716e (1981).
Derwent Abstract 95-070280/10 (1995).
Einhorn, et al., Liebigs Ann. Chem., vol 343, pp. 223-282 (1905).
Kontoghiorghes, G. J. Toxicology Letters, vol. 80, pp. 1-18 (1995).
Ryabukhin, et al., Translation form Koord. Khim., vol. 13, No. 7, pp. 869-874 (1987).
Ryabukhin, et al., Translation from Khim. Geterot. Soed., vol. 3, pp. 406-410 (1983).
Wagner, et al., Pharmazie, vol. 35, pp. 48-50 (1980).
Wagner, et al., Z. Chem., vol. 21, p. 261 (1981).

Cited By (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050080120A1 (en) * 2001-11-06 2005-04-14 Rene Lattmann 4-[3,5-bis-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid derivatives for treating an excess of metal in the body
US7074815B2 (en) * 2001-11-06 2006-07-11 Novartis Ag 4-[3,5-bis-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid derivatives for treating an excess of metal in the body
US20050008699A1 (en) * 2003-07-11 2005-01-13 Fred Wehling Effervescent glucosamine composition
US20080139480A1 (en) * 2003-12-19 2008-06-12 Bruemmendorf Tim H Combination Of (A) N--4-(3- Pyridyl)-2-Pyrimidine-Amine And (B) At Least One Hypusination Inhibitor And The UseThereof
WO2005058320A1 (en) * 2003-12-19 2005-06-30 Novartis Ag COMBINATION OF (a) N-{5-[4-(4-METHYL-PIPERAZINO-METHYL)-BENZOYLAMIDO]-2METHYLPHENYL}-4-(3-PYRIDYL)-2-PYRIMIDINE-AMINE AND (b) AT LEAST ONE HYPUSINATION INHIBITOR AND THE USE THEREOF
US20080114001A1 (en) * 2005-01-28 2008-05-15 Manley Paul W Use of Pyrimidylaminobenzamides for the Treatment of Diseases that Respond to Modulation of Tie-2 Kinase Activity
WO2006084683A1 (en) * 2005-02-10 2006-08-17 Novartis Ag Methods for improving drug disposition
US20080187510A1 (en) * 2005-02-10 2008-08-07 Camenisch Gian P Methods for Improving Drug Disposition
US20090306160A1 (en) * 2005-02-10 2009-12-10 Camenisch Gian P Methods for improving drug disposition
US20080199428A1 (en) * 2005-05-31 2008-08-21 Alberti Daniele M Treatment of Liver Diseases in Which Iron Plays a Role in Pathogenesis
US20130109730A1 (en) * 2005-05-31 2013-05-02 Novartis Ag Treatment of liver diseases in which iron plays a role in pathogenesis
US20100098662A1 (en) * 2005-05-31 2010-04-22 Alberti Daniele M Treatment of liver diseases in which iron plays a role in pathogenesis
JP2009513688A (ja) * 2005-11-01 2009-04-02 ノバルティス アクチエンゲゼルシャフト シンチグラフィー法
RU2469721C2 (ru) * 2006-05-09 2012-12-20 Новартис Аг Комбинация, включающая комплексон железа и противоопухолевый агент, и ее применение
US20090317489A1 (en) * 2006-05-09 2009-12-24 Hanspeter Nick Combination Comprising an Iron Chelator and an Anti-Neoplastic Agent and Use Thereof
US20110159114A1 (en) * 2006-05-09 2011-06-30 Hanspeter Nick Combination comprising an iron chelator and an anti-neoplastic agent and use thereof
EP2272511A1 (en) 2006-05-09 2011-01-12 Novartis AG Combination comprising an iron chelator and an anti-neoplastic agent and use thereof
EP2255805A1 (en) 2006-05-23 2010-12-01 Novartis AG Deferasirox for the treatment of hereditary hemochromatosis
US20110105575A1 (en) * 2006-05-23 2011-05-05 Hanspeter Nick Method of treatment of hereditary hemochromatosis
EP2412371A1 (en) 2006-07-13 2012-02-01 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center Compositions comprising iron chelators (deferiprone/deferasirox) for use in the treatment of mucormycosis and other fungal diseases
US20100129434A1 (en) * 2006-07-13 2010-05-27 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Compositions and methods for the treatment of mucormycosis and other fungal diseases
US8946272B2 (en) * 2006-11-29 2015-02-03 Novartis Ag Plymorphic forms of deferasirox (ICL670A)
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EP2253317A2 (en) 2007-05-22 2010-11-24 Novartis AG Triazol compounds for treating biofilm formation
US8592473B2 (en) 2007-05-22 2013-11-26 Novartis Ag Triazol compounds for treating biofilm formation
RU2478385C2 (ru) * 2007-05-22 2013-04-10 Новартис Аг Соединения триазола для лечения образования биопленок
US20090082412A1 (en) * 2007-09-26 2009-03-26 Protia, Llc Deuterium-enriched deferasirox
US8592476B2 (en) 2007-10-31 2013-11-26 Proteotech, Inc. Compounds, compositions, and methods for the treatment of β-amyloid diseases and synucleinopathies
US8829198B2 (en) 2007-10-31 2014-09-09 Proteotech Inc Compounds, compositions and methods for the treatment of beta-amyloid diseases and synucleinopathies
US20090111863A1 (en) * 2007-10-31 2009-04-30 Esposito Luke A Compounds, Compositions and Methods for the Treatment of Beta-Amyloid Diseases and Synucleinopathies
US8563590B2 (en) 2008-03-05 2013-10-22 Proteotech, Inc. Compounds, compositions and methods for the treatment of islet amyloid polypeptide (IAPP) accumulation in diabetes
US20110097413A1 (en) * 2008-04-21 2011-04-28 Actavis Group Ptc Ehf Solid state forms of deferasirox salts and process for the preparation thereof
WO2009130604A3 (en) * 2008-04-21 2009-12-30 Actavis Group Ptc Ehf Solid state forms of deferasirox salts and process for the preparation thereof
US20110171138A1 (en) * 2008-06-02 2011-07-14 Actavis Group Ptc Ehf Substantially pure deferasirox and processes for the preparation thereof
WO2009147529A1 (en) * 2008-06-02 2009-12-10 Actavis Group Ptc Ehf Substantially pure deferasirox and processes for the preparation thereof
US10751304B2 (en) 2008-10-10 2020-08-25 The Board Of Trustees Of The Leland Stanford Junior University Topical and transdermal delivery of HIF-1 modulators to prevent and treat chronic wounds
US11160775B2 (en) 2008-10-10 2021-11-02 The Board Of Trustees Of The Leland Stanford Junior University Topical and transdermal delivery of HIF-1 modulators to prevent and treat chronic wounds
US8444985B2 (en) 2009-03-19 2013-05-21 Los Angeles Biomedical Research Institute at Harbor-ULCA Medical Center Vaccine compositions and methods for treatment of mucormycosis and other fungal diseases
US20100285024A1 (en) * 2009-03-19 2010-11-11 Ibrahim Ashraf S Vaccine compositions and methods for treatment of mucormycosis and other fungal diseases
US20120245361A1 (en) * 2009-12-07 2012-09-27 Mapi Pharma Hk Limited Processes for the preparation of deferasirox, and deferasirox polymorphs
US8772503B2 (en) * 2009-12-07 2014-07-08 Mapi Pharma Ltd. Processes for the preparation of deferasirox, and deferasirox polymorphs
EP2509423A4 (en) * 2009-12-07 2013-07-31 Mapi Pharma Ltd PROCESS FOR THE PREPARATION OF DEFERASIROX AND DEFERASIROX POLYMORPHO
WO2011070560A1 (en) 2009-12-07 2011-06-16 Mapi Pharma Hk Limited Processes for the preparation of deferasirox, and deferasirox polymorphs
WO2012025935A2 (en) 2010-08-25 2012-03-01 Ramamohan Rao Davuluri A process for the preparation of 2-(2-hydroxyphenyl)-benz[1,3]oxazin-4-one and its use for preparation of 4-[3, 5-bis (2-hydroxyphenyl)-1h-1, 2, 4-triazol-1-yl] benzoic acid
EP2632907A4 (en) * 2010-08-25 2014-07-09 Davuluri Ramamohan Rao PROCESS FOR THE PREPARATION OF 2- (2-HYDROXYPHENYL) -BENZ [1,3] OXAZIN-4-ONE AND USE THEREOF FOR THE PREPARATION OF 4- [3,5-BIS (2-HYDROXYPHENYL) -1H-1 ACID 2,4-TRIAZOL-1-YL] -BENZOIC
WO2012069946A1 (en) 2010-11-24 2012-05-31 Alembic Pharmaceuticals Limited Process for the preparation of deferasirox
US9018389B2 (en) 2010-11-24 2015-04-28 Alembic Pharmaceuticals, Ltd. Process for the preparation of Deferasirox
US9796605B2 (en) 2011-01-14 2017-10-24 Disease Adsorption System Technologies Co., Ltd. Polymeric iron chelating agent
AU2014224252B2 (en) * 2013-03-06 2016-09-22 Biocon Limited Process for the preparation of Deferasirox
CN103454370A (zh) * 2013-09-11 2013-12-18 中美华世通生物医药科技（武汉）有限公司 一种利用hplc测定原料药中苯肼类化合物残留的方法
WO2016203488A1 (en) * 2015-06-16 2016-12-22 Havaldar Freddy H Preparation of novel deferasirox analogues for antimalarial activity
WO2017158559A1 (en) 2016-03-17 2017-09-21 Lupin Limited Compositions of deferasirox
US11331288B2 (en) 2017-09-14 2022-05-17 The Board Of Trustees Of The Leland Stanford Junior University Conditioning irradiated tissue for increasing vascularity
US12303475B2 (en) 2017-09-14 2025-05-20 The Board Of Trustees Of The Leland Stanford Junior University Conditioning irradiated tissue for increasing vascularity

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